The purpose of this proposal is a study of the mechanisms of fibrosis in man with special emphasis on a major sclerosing condition, scleroderma. The laboratories of the principal investigator have been engaged in a multidisciplinary approach to the pathogenesis of scleroderma since 1965. Hypotheses which encompass all known abnormalities in scleroderma have been devised to link the biochemical abnormalities of connective tissue with the microvascular abnormalities. In recent years this laboratory has published direct evidence that the scleroderma fibroblast produces more collagen than the normal fibroblast; also, direct data of both morphologic (capillary patterns) and physiologic (capillary blood flow) nature have documented a microvascular abnormality in Raynaud's syndrome-scleroderma, which we have come to think of as a continuum. This renewal proposal will expand the cell culture and the microvascular observations and seek common denominators between the two areas designed to ask two types of questions: 1) Does the abnormality in the fibroblast incite or perpetuate the microvascular disorder? and 2) Does the microvascular defect direct the abnormality in fibroblast metabolism? To accomplish these goals, biochemical and immunochemical investigation of cell culture models of scleroderma will be carried out and the milieu of the cell culture environment will be altered to simulate the altered microvascular environment observed in these patients. Coordinated studies of capillary morphology and capillary blood flow (133Xe technique) will be carried out in these same subjects. Subjects with rheumatoid arthritis and systemic lupus erythematosus will serve as comparison disease controls. Widefield capillary microscopy, microcinephotography, and the culture of endothelial, vascular smooth muscle, and mononuclear immunocompetent cells will complement the existing approaches to link the biochemical and microvascular abnormalities.